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TNF- suppresses the expression of clock genes by interfering with E-box-mediated transcription
Thomas Birchler*,, and
*Division of Clinical Immunology, University Hospital Zurich, Haeldeliweg 4, CH-8044 Zurich, Switzerland; Institute of Biochemistry, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland; and Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
Edited by Charles A. Dinarello, University of Colorado Health Sciences Center, Denver, CO, and approved June 15, 2007
Received for publication February 22, 2007.
Production of TNF- and IL-1 in infectious and autoimmune diseasesis associated with fever, fatigue, and sleep disturbances, whichare collectively referred to as sickness behavior syndrome.In mice TNF- and IL-1 increase nonrapid eye movement sleep.Because clock genes regulate the circadian rhythm and therebylocomotor activity and may alter sleep architecture we assessedthe influence of TNF- on the circadian timing system. TNF- isshown here to suppress the expression of the PAR bZip clock-controlledgenes Dbp, Tef, and Hlf and of the period genes Per1, Per2,and Per3 in fibroblasts in vitro and in vivo in the liver ofmice infused with the cytokine. The effect of TNF- on clockgenes is shared by IL-1, but not by IFN-, and IL-6. Furthermore,TNF- interferes with the expression of Dbp in the suprachiasmaticnucleus and causes prolonged rest periods in the dark when miceshow spontaneous locomotor activity. Using clock reporter genesTNF- is found here to inhibit CLOCK-BMAL1-induced activationof E-box regulatory elements-dependent clock gene promoters.We suggest that the increase of TNF- and IL-1, as seen in infectiousand autoimmune diseases, impairs clock gene functions and causesfatigue.
Author contributions: G.C. and S.P. contributed equally to thiswork; T.B. and A.F. contributed equally to this work; G.C.,S.P., I.T., T.B., and A.F. designed research; G.C., S.P., P.K.,C.J., T.B., and A.F. performed research; C.J. and I.T. contributednew reagents/analytic tools; G.C., S.P., I.T., T.B., and A.F.analyzed data; and T.B. and A.F. wrote the paper.
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